1. Field of the Invention
The present invention relates to a novel estradiol derivative-chlorambucil conjugate. More particularly, the present invention relates to a conjugate comprising a reaction product of an estradiol derivative and chlorambucil, a process for preparing the same, and a pharmaceutical composition comprising the conjugate.
2. Description of the Related Art
There are many conventional antitumor agents which inherently have strong antitumor effects, but in fact do not sufficiently exhibit their inherent effects. The main reason is that the amount of administeration is limited due to their side effects. One of the attempts to solve the above problem is to bind the antitumor agent with a carrier having specific affinity to the tumor sites, and thereby form a conjugate of an antitumor agent and a carrier. The attempt intended to accumulate the antitumor agent specifically to the tumor sites and effectively exhibit the antitumor effect while reducing the side effects.
On the basis of the above conception, an estradiol-chlorambucil conjugate and an antitumor agent containing mainly the conjugate were already proposed in U.S. Pat. No. 4,261,910 and U.S. Pat. No. 4,332,797. The antitumor agent can accumulate specifically to the tumor sites and exhibit a strong antitumor effect thereat. Further, its influence on normal cells is extremely small.
Recently, H. Kosano, et al. reported that the above estradiol-chlorambucil conjugate inhibits the estrogen effect to promote the growth of MCF-7 (human breast carcinoma cell, its growth is promoted by estrogen), irreversibly or over an extremely long period (Hiroshi Kosano, et al., Cancer Research 52, 1187-1191, 1992). The reason thereof is suggested that the decrease in estrogen receptors causes a loss of the estrogen sensitivity of the cell, followed by inhibition of transforming growth factor (TGF)-.alpha. secretion and succeeding inhibition of the cell growth. It is also suggested that the structure of the conjugate is necessary for the conjugate to exhibit the above effects on the estrogen receptors and inhibit the secretion of TGF-.alpha.. That is, it is not suggested that the above effects are caused by chlorambucil liberated in the process of the conjugate degradation.
Further, U.S. Pat. No. 4,921,849 discloses an injection prepared by dissolving the above estradiol-chlorambucil conjugate in an ester of iodinated poppy oil fatty acid. The injection enables the conjugate to reside for a long period at the tumor sites and to exhibit its full pharmacological effects. Further, U.S. Pat. No. 4,885,290 discloses an immunoregulator containing as an active ingredient the above conjugate which selectively suppresses immunoreactions caused specifically by isoantigen. Thus, the estradiol-chlorambucil conjugate exhibits selective physiological activities, such as a selective antitumor effect, a selective immunosuppressive effect and the like.
When an antitumor agent is administered for a long period, however, even weak side effects, which do not pose a problem with short term administration, in fact accumulate and become significant problems. In particular, a cancer patient lacks vital force, and therefore, such an accumulation of weak side effects is intensified. One of the problems with the conjugate is an adverse effect by a slight amount of estrogen released in the body from the estradiol-chlorambucil conjugate. For example, with long term administration of the conjugate, the slight amount of the released estrogen accumulates and may cause side effects such as gynecomastia, mastosis, nipple pain, genital bleeding, and the like. These estrogenic activities may be a problem even in the injections, immunoregulator or the like containing the above conjugate.